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Manganese regulates caspase-3 gene promoter activity by inducing Sp1 phosphorylation in PC12 cells

Atsuhiro Uchida1, Kentaro Oh-hashi, Kazutoshi Kiuchi

  • 1United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu 501-1194, Japan.

Toxicology
|September 15, 2012
PubMed

Insights

Chronic manganese exposure triggers neuronal apoptosis via caspase-3 activation. This study reveals Sp1 phosphorylation is crucial for manganese-induced caspase-3 gene expression, offering insights into manganism.

Area of Science:

  • Neurotoxicology
  • Molecular Biology
  • Cellular Apoptosis

Background:

  • Chronic manganese exposure leads to parkinsonian-like symptoms (manganism) by damaging the dopaminergic system.
  • Manganese induces apoptosis in PC12 cells, involving caspase cascade activation and DNA fragmentation.
  • Caspase-3 is a key executioner of neuronal apoptosis, and its expression increases with manganese treatment.

Purpose of the Study:

  • To elucidate the molecular mechanisms regulating caspase-3 expression in manganese-treated PC12 cells.
  • To identify regulatory elements in the caspase-3 gene responsive to manganese.
  • To investigate the role of Sp1 transcription factor in manganese-induced caspase-3 activation.

Main Methods:

  • Characterization of the 5'-flanking region of the rat caspase-3 gene.
  • Analysis of Sp1 binding sites and their role in promoter activity.
  • Assessment of Sp1 phosphorylation and DNA binding activity following manganese exposure.
  • Evaluation of caspase-3 promoter activity using wild-type and mutant Sp1 constructs.

Main Results:

  • A manganese-responsive region with three Sp1 binding sites was identified in the caspase-3 gene promoter.
  • Manganese treatment increased Sp1 phosphorylation and its DNA binding activity.
  • Overexpression of a non-phosphorylatable Sp1 mutant reduced manganese-induced caspase-3 promoter activity.

Conclusions:

  • Sp1 phosphorylation is essential for the transactivation of the caspase-3 gene by manganese.
  • This finding provides a molecular basis for manganese-induced neuronal apoptosis and manganism.
  • Targeting Sp1 phosphorylation may offer therapeutic strategies for manganese neurotoxicity.

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